Abstract:

A subject-matter of the present invention is pharmaceutical compositions
comprising, in combination, at least one active ingredient chosen from
(S)-(-)-N-[4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)b-
utyl]-N-methylbenzamide and pharmaceutically acceptable salts thereof and
at least one second active ingredient chosen from
(S)-(+)-1-[4-(3-(dimethylamino)propyl)]-1-(4-fluorophenyl)-1,3-dihydro-2--
benzofuran-5-carbonitrile and pharmaceutically acceptable salts thereof.

Claims:

1. A combination comprising at least one active ingredient chosen from
saredutant and pharmaceutically acceptable salts thereof and at least one
second active ingredient chosen from escitalopram and pharmaceutically
acceptable salts thereof.

2. The combination according to claim 1, wherein said at least one active
ingredient and said at least one second active ingredient are
administered simultaneously, separately or spread out over time.

3. The combination according to claim 2, wherein said at least one active
ingredient and said at least one second active ingredient are
administered simultaneously.

4. The combination according to claim 2, wherein said at least one active
ingredient and said at least one second active ingredient are
administered separately.

5. The combination according to claim 2, wherein said at least one active
ingredient and said at least one second active ingredient are
administered spread out over time.

6. A pharmaceutical composition comprising at least one active ingredient
chosen from saredutant and pharmaceutically acceptable salts thereof and
at least one second active ingredient chosen from escitalopram and
pharmaceutically acceptable salts thereof in combination with at least
one pharmaceutically acceptable excipient.

7. The composition according to claim 6, wherein said at least one active
ingredient and said at least one second active ingredient are
administered simultaneously, separately or spread out over time.

8. The composition according to claim 7, wherein said at least one active
ingredient and said at least one second active ingredient are
administered simultaneously.

9. The composition according to claim 7, wherein said at least one active
ingredient and said at least one second active ingredient are
administered separately.

10. The composition according to claim 7, wherein said at least one active
ingredient and said at least one second active ingredient are
administered spread out over time.

11. A method of treatment of a mood disorder in a patient comprising
administering to the patient a therapeutically effective amount of a
combination of at least one active ingredient chosen from saredutant and
pharmaceutically acceptable salts thereof and at least one second active
ingredient chosen from escitalopram and pharmaceutically acceptable salts
thereof optionally in combination with one or more pharmaceutically
acceptable excipients.

12. The method according to claim 11, wherein the mood disorder is major
depressive disorder.

13. The method according to claim 12, wherein the major depressive
disorder is sexual dysfunctions associated with a major depressive
disorder.

14. The method according to claim 11, wherein the mood disorder is
resistant depressive disorder.

15. The method according to claim 11, wherein the mood disorder is
dysthymic disorder.

16. The method according to claim 11, wherein the mood disorder is
depressive disorder not otherwise specified.

17. The method according to claim 11, wherein the mood disorder is bipolar
I disorder.

18. The method according to claim 11, wherein the mood disorder is bipolar
II disorder.

19. The method according to claim 11, wherein the mood disorder is
cyclothymic disorder.

20. The method according to claim 11, wherein the mood disorder is bipolar
disorder not otherwise specified.

Description:

[0001]This application is a continuation of U.S. application Ser. No.
11/830,293, filed Jul. 30, 2007, which is incorporated herein by
reference in its entirety; which claims the benefit of priority of French
Patent Application No. FR07/00,863, filed Feb. 7, 2007.

[0002]A subject-matter of the present invention is pharmaceutical
compositions comprising, in combination, at least one active ingredient
chosen from
(S)-(-)-N-[4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)b-
utyl]-N-methylbenzamide and pharmaceutically acceptable salts thereof and
at least one second active ingredient chosen from
(S)-(+)-1-[4-(3-(dimethylamino)propyl)]-1-(4-fluorophenyl)-1,3-dihydro-2--
benzofuran-5-carbonitrile and pharmaceutically acceptable salts thereof.

[0003](S)-(-)-N-[4-(4-Acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophe-
nyl)butyl]-N-methylbenzamide, the international nonproprietary name of
which is saredutant, of formula:

##STR00001##

hereinafter referred to as compound A, and its pharmaceutically acceptable
salts have been described as nonpeptide antagonists of the NK2
receptors of neurokinin A (Life Sciences, 1992, 50(15), PL101-PL106) and
can be prepared according to Patents EP 0 474 561 or U.S. Pat. No.
5,236,921.

[0004](S)-(+)-1-[4-(3-(dimethylamino)propyl)]-1-(4-fluorophenyl)-1,3-dihyd-
ro-2-benzofuran-5-carbonitrile, the international non-proprietary name of
which is escitalopram, of formula:

##STR00002##

hereinafter referred to as compound B, and its pharmaceutically acceptable
salts have been described as selective serotonin reuptake inhibitors
(SSRI) and can be prepared according to Patent EP 0 347 066 or U.S. Pat.
No. 4,943,590.

[0005]It has now been found, surprisingly, that the combination of
saredutant with escitalopram may significantly enhance the
pharmacological effects of each of the compounds used alone, in
particular the antidepressant effects.

[0006]In another aspect of this invention there is provided a
pharmaceutical composition comprising a combination of at least one
active ingredient chosen from saredutant and pharmaceutically acceptable
salts thereof and at least one second active ingredient chosen from
escitalopram and pharmaceutically acceptable salts thereof, further in
combination with at least one pharmaceutically acceptable excipient.

[0007]In another aspect of this invention there are also provided methods
of treatment of various mood disorders and anxiety disorders using the
compositions of this invention as specifically disclosed hereinbelow.

[0008]The salts are the salts with conventional pharmaceutically
acceptable inorganic or organic acids, such as the hydrochloride, the
hydrobromide, the sulfate, the hydrogensulfate, the dihydrogenphosphate,
the methanesulfonate, the methyl sulfate, the acetate, the oxalate, the
maleate, the fumarate, the succinate, the naphthalene-2-sulfonate, the
glyconate, the gluconate, the citrate, the isethionate, the
benzenesulfonate or the para-toluenesulfonate.

[0009]It has now been found, surprisingly, that the combination of
saredutant with escitalopram may significantly enhance the
pharmacological effects of each of the compounds used alone, in
particular the antidepressant effects.

[0010]Thus, the pharmaceutical compositions comprising such combination
can be of use in the manufacture of medicaments intended for the
prevention and treatment of mood disorders, such as major depressive
disorder, resistant depressive disorder, dysthymic disorder, depressive
disorder not otherwise specified, bipolar I disorder, bipolar II
disorder, cyclothymic disorder, bipolar disorder not otherwise specified,
mood disorder due to a general medical condition, mood disorder induced
by a substance, mood disorder not otherwise specified; anxiety disorders,
such as panic attack, agoraphobia, social phobia, obsessive-compulsive
disorder, post-traumatic stress condition, acute stress condition,
generalized anxiety disorder or anxiety disorder induced by a substance.

[0011]In particular, the pharmaceutical compositions comprising such
combination can be of use in the manufacture of medicaments intended for
the prevention and treatment of a major depressive disorder.

[0012]In particular again, the pharmaceutical compositions comprising such
combination can be of use in the manufacture of medicaments intended for
the treatment of sexual dysfunctions associated with a major depressive
disorder.

[0013]The term "sexual dysfunctions" is understood to mean any pathology
as defined by the American Psychiatric Association--DSM-IV-TR, Diagnostic
and Statistical Manual of Mental Disorders, 4th edition, revised text
(Washington DC, 2000), pages 617-654, and which includes disorders of
sexual desire (that is to say, the disorder: fall in sexual desire, and
the disorder: sexual aversion), disorders of sexual arousal (that is to
say, female sexual arousal disorder and male erectile disorder), orgasmic
disorders (that is to say, female orgasmic disorder, male orgasmic
disorder and premature ejaculation), painful sexual disorders (that is
say, dyspareunia and vaginismus), sexual dysfunction due to a general
medial condition, sexual dysfunction induced by a substance and sexual
dysfunctions not otherwise specified.

[0014]Thus, according to one of its aspects, a subject-matter of the
present invention is pharmaceutical compositions comprising, in
combination, at least one active ingredient chosen from saredutant and
pharmaceutically acceptable salts thereof and at least one second active
ingredient chosen from escitalopram and pharmaceutically acceptable salts
thereof, and also at least one pharmaceutically acceptable excipient.

[0015]According to another of its aspects, a subject-matter of the present
invention is the combination of at least one active ingredient chosen
from saredutant and pharmaceutically acceptable salts thereof and at
least one second active ingredient chosen from escitalopram and
pharmaceutically acceptable salts thereof.

[0016]According to another of its aspects, a subject-matter of the present
invention is the use of a pharmaceutical composition comprising, in
combination, at least one active ingredient chosen from saredutant and
pharmaceutically acceptable salts thereof and at least one second active
ingredient chosen from escitalopram and pharmaceutically acceptable salts
thereof, in the manufacture of medicaments intended for the prevention
and treatment of mood disorders chosen from major depressive disorder,
resistant depressive disorder, dysthymic disorder, depressive disorder
not otherwise specified, bipolar I disorder, bipolar II disorder,
cyclothymic disorder, bipolar disorder not otherwise specified, mood
disorder due to a general medical condition, mood disorder induced by a
substance, mood disorder not otherwise specified; anxiety disorders,
chosen from panic attack, agoraphobia, social phobia,
obsessive-compulsive disorder, post-traumatic stress condition, acute
stress condition, generalized anxiety disorder or anxiety disorder
induced by a substance.

[0017]In particular, a subject-matter of the present invention is the use
of a pharmaceutical composition comprising, in combination, at least one
active ingredient chosen from saredutant and pharmaceutically acceptable
salts thereof and at least one second active ingredient chosen from
escitalopram and pharmaceutically acceptable salts thereof, in the
manufacture of medicaments intended for the prevention and the treatment
of a major depressive disorder.

[0018]In particular again, a subject-matter of the present invention is
the use of a pharmaceutical composition comprising, in combination, at
least one active ingredient chosen from saredutant and pharmaceutically
acceptable salts thereof and at least one second active ingredient chosen
from escitalopram and pharmaceutically acceptable salts thereof, in the
manufacture of medicaments intended for the treatment of sexual
dysfunctions associated with a major depressive disorder.

[0019]According to another of its aspects, a subject-matter of the present
invention is the use of the combination of at least one active ingredient
chosen from saredutant and pharmaceutically acceptable salts thereof and
at least one second active ingredient chosen from escitalopram and
pharmaceutically acceptable salts thereof, in the manufacture of
medicaments intended for the prevention and treatment of mood disorders
chosen from major depressive disorder, resistant depressive disorder,
dysthymic disorder, depressive disorder not otherwise specified, bipolar
I disorder, bipolar II disorder, cyclothymic disorder, bipolar disorder
not otherwise specified, mood disorder due to a general medical
condition, mood disorder induced by a substance, mood disorder not
otherwise specified; anxiety disorders, chosen from panic attack,
agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic
stress condition, acute stress condition, generalized anxiety disorder or
anxiety disorder induced by a substance.

[0020]The excipients are chosen, according to the pharmaceutical form and
the method of administration desired, from the usual excipients which are
known to a person skilled in the art.

[0021]In the pharmaceutical compositions of the present invention for
oral, sublingual, subcutaneous, intramuscular, intravenous, topical,
local, intratracheal, intranasal, transdermal or rectal administration,
the active principles can be administered in unit administration form, as
a mixture with conventional pharmaceutical excipients, to animals and
human beings for the prevention or treatment of the above disorders or
diseases.

[0023]In the pharmaceutical compositions of the present invention, the
active principle or the active principles are generally formulated in
dosage units containing from 2.5 to 500 mg, advantageously from 10 to 250
mg and preferably from 10 to 150 mg of the said active principle per
dosage unit for daily administrations. There may be particular case in
which higher or lower dosages are appropriate; such dosages do not depart
from the context of the invention. According to the usual practice, the
dosage that is appropriate for each patient is determined by the doctor
according to the mode of administration and the weight and response of
the said patient.

[0024]According to another aspect of the invention, the compound A and the
compound B according to the invention can be administered simultaneously,
separately or spread out over time.

[0025]The term "simultaneous use" is understood to mean the administration
of the compounds of the composition according to the invention comprise
within one and the same pharmaceutical form.

[0026]The term "separate use" is understood to mean the administration, at
the same time, of the two compounds of the composition according to the
invention, each comprised within a separate pharmaceutical form.

[0027]The term "use spread out over time" is understood to mean the
successive administration of the first compound of the composition
according to the invention, comprised within a pharmaceutical form, and
then of the second compound of the composition according to the
invention, comprised within a separate pharmaceutical form.

[0028]In the case of this "use spread out over time", the period of time
elapsed between the administration of the first compound of the
composition according to the invention and the administration of the
second compound of the same composition according to the invention
generally does not exceed 24 hours.

[0029]The unit pharmaceutical forms comprising either just one of the
constituent compounds of the composition according to the invention or
the combination of the 2 compounds which can be employed in the various
types of use described above may, for example, be appropriate for oral,
nasal, parenteral or transdermal administration.

[0030]Consequently, in the case of a "separate use" and of a "use spread
out over time", two separate pharmaceutical forms may be intended for the
same route of administration or for a different route of administration
(oral and transdermal or oral and nasal or parenteral and transdermal,
and the like).

[0031]The invention thus also relates to a kit comprising the compound A
and the compound B according to the invention in which the said compound
A and the compound B according to the invention are in separate
compartments and in similar or different packagings and are intended to
be administered simultaneously, separately or spread out over time.

[0032]Specifically and without implied limitation, the effects of a
combination according to the invention of the compound A and of
escitalopram are studied during clinical studies.

EXAMPLE 1

[0033]The effects of a combination according to the invention of
saredutant with escitalopram are evaluated during multicentric randomized
double-blind clinical studies lasting eight weeks in which a group
receiving a fixed dose of saredutant once daily in combination with a
fixed dose of escitalopram once daily is compared with a group receiving
saredutant placebo in combination with a fixed dose of escitalopram and
with another group receiving saredutant placebo in combination with
escitalopram placebo.

[0034]These clinical studies are carried out on adult male or female
patients exhibiting a major depressive disorder as defined by the
criteria of the Diagnostic and Statistical Manual of Mental Disorders,
4th edition, revised text (DSM-IV-TR), and confirmed by the criteria of
the Mini International Neuropsychiatric Interview (MINI), Lecrubier Y. et
al., Eur. Psychiatr., 1997, 12, 224-231.

[0035]The change in the total score on the Hamilton Depression Rating
Scale comprising 17 items (HAM-D) between the final visit (expected on
the 56th day) and the first visit (before the beginning of the treatment)
is measured with respect to the placebo group. The Hamilton Depression
Rating Scale is defined by Hamilton M., J. Neurol. Neurosurg. Psychiatry,
1960, 23, 56-62.

[0036]The change in the total score of the CSFQ comprising 14 items
(Changes in Sexual Functioning Questionnaire) between the final visit
(expected on the 56th day) and the first visit (before the beginning of
the treatment) is also measured with respect to the placebo group. The
CSFQ is defined by Clayton A H et al., Psychopharmacol. Bull., 1997, 33,
731-745.

EXAMPLE 2

[0037]A pharmaceutical composition in accordance with this invention in
the form of a capsule comprising 100 mg of saredutant was prepared
including the following pharmaceutically acceptable excipients.

[0038]Although the invention has been illustrated by certain of the
preceding examples, it is not to be construed as being limited thereby;
but rather, the invention encompasses the generic area as hereinbefore
disclosed. Various modifications and embodiments can be made without
departing from the spirit and scope thereof.